The present invention relates to methods for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth.
Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness.
As is well-known in the art, hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three main stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased. The next phase, telogen, is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. Wherein hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness.
There have been many attempts in the literature to invoke the regrowth of hair by, for example, the promotion or prolongation of anagen. Currently, there are two drugs approved by the United States Food and Drug Administration for the treatment of male pattern baldness: topical minoxidil (marketed as Rogaine(copyright) by Pharmacia and Upjohn), and oral finasteride (marketed as Propecia(copyright) by Merck and Co., Inc.). For several reasons, however, including safety concerns and/or lack of efficacy, the search for efficacious hair growth inducers is ongoing.
Interestingly, it is known that the thyroid hormone known as thyroxine (xe2x80x9cT4xe2x80x9d) converts to thyronine (xe2x80x9cT3xe2x80x9d) in human skin by deiodinase I, a selenoprotein. Selenium deficiency causes a decrease in T3 levels due to a decrease in deiodinase I activity; this reduction in T3 levels is strongly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of administration of T4. See, e.g., Berman, xe2x80x9cPeripheral Effects of L-Thyroxine on Hair Growth and Coloration in Cattlexe2x80x9d, Journal of Endocrinology, Vol. 20, pp. 282-292 (1960); and Gunaratnam, xe2x80x9cThe Effects of Thyroxine on Hair Growth in the Dogxe2x80x9d, J. Small Anim. Pract., Vol. 27, pp. 17-29 (1986). Furthermore, T3 and T4 have been the subject of several patent publications relating to treatment of hair loss. See, e.g., Fischer et al., DE 1,617,477, published Jan. 8, 1970; Mortimer, GB 2,138,286, published Oct. 24, 1984; and Lindenbaum, WO 96/25943, assigned to Life Medical Sciences, Inc., published Aug. 29, 1996.
Unfortunately, however, administration of T3 and/or T4 to treat hair loss is not practicable because these thyroid hormones are also known to induce significant cardiotoxicity. See, e.g., Walker et al., U.S. Pat. No. 5,284,971, assigned to Syntex, issued Feb. 8, 1994 and Emmett et al., U.S. Pat. No. 5,061,798, assigned to Smith Kline and French Laboratories, issued Oct. 29, 1991. Surprisingly, however, the present inventors have discovered compounds which promote hair growth without inducing cardiotoxicity. Consistent with this discovery, but without intending to be limited by theory, the present inventors have surprisingly discovered that the compounds useful in the present invention interact strongly with hair-selective thyroid hormone receptors but interact less strongly, or not at all, with heart-selective hormone receptors. These unique properties are, of course, not shared with T3 and/or T4. Accordingly, the compounds described for use in the methods and compositions herein are cardiac-sparing compounds useful for treating hair loss, including arresting and/or reversing hair loss and promoting hair growth.
The present invention relates to methods for treating hair loss comprising administering a compound which has been found by the present inventors to be particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The compounds utilized in the present method have the structure: 
and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and n are defined herein.
The present invention relates to methods of using compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth.
In addition to discovering that the present compounds are useful for treating hair loss, the present inventors have also surprisingly discovered that the preferred compounds are cardiac-sparing. The preferred compounds useful in the method of the present invention are therefore, as defined herein below, cardiac-sparing.
Publications and patents are referred to throughout this disclosure. All references cited herein are hereby incorporated by reference.
All percentages, ratios, and proportions used herein are by weight unless otherwise specified.
In the description of the invention various embodiments and/or individual features are disclosed. As will be apparent to the ordinarily skilled practitioner all combinations of such embodiments and features are possible and can result in preferred executions of the invention.
As used herein, wherein any variable, moiety, group, or the like occurs more than one time in any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence.
The following is a list of definitions for terms used herein:
As used herein, xe2x80x9cacylxe2x80x9d refers to the group xe2x80x94C(O)R, where R is lower alkyl or cycloalkyl, for example, acetyl, propionyl, cyclopropionyl, butanoyl, and the like.
As used herein, xe2x80x9calkoxyxe2x80x9d is an oxygen radical having an alkyl substituent. Examples of alkoxy radicals include xe2x80x94O-methyl and xe2x80x94O-ethyl.
As used herein, xe2x80x9calkylxe2x80x9d is a saturated, straight or branched chain monovalent hydrocarbon radical. Unless otherwise specified, alkyls have from 1 to about 8 carbon atoms (C1-C8). Preferred alkyls include, for example, methyl, ethyl, propyl, iso-propyl, tert-butyl, n-butyl, sec-butyl, iso-butyl, n-hexyl, and n-octyl.
As used herein, xe2x80x9carylxe2x80x9d refers to a monovalent unsaturated aromatic carbocyclic radical having a single ring (e.g., phenyl) or two rings (e.g., naphthyl or biphenyl), which may optionally be mono-, di-, or tri-substituted, independently, with hydroxy, xe2x80x94COOH, lower alkyl, lower alkoxy, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, and/or cyano.
As used herein, xe2x80x9cbiohydrolyzable amidesxe2x80x9d are amides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
As used herein, xe2x80x9cbiohydrolyzable estersxe2x80x9d are esters of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
As used herein, xe2x80x9cbiohydrolyzable imidesxe2x80x9d are imides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
As used herein, xe2x80x9ccycloalkylxe2x80x9d is a monovalent monocyclic hydrocarbon radical having from three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
As used herein, xe2x80x9chalogenxe2x80x9d refers to chlorine, bromine, iodine, and fluorine, preferably chlorine, bromine, and iodine, more preferably chlorine and iodine, and most preferably iodine.
As used herein, xe2x80x9cheteroarylxe2x80x9d refers to a monovalent aromatic carbocyclic radical having from 1 to 3 heteroatoms within a single ring, (e.g., pyridyl, imidazolyl, thiazolyl, pyrimidine, oxazolyl, and the like), which may optionally be mono-, di-, or tri-substituted, independently, with hydroxy, xe2x80x94COOH, lower alkyl, lower alkoxy, nitro, amino, alkylamino, dialkylamino, trifluoromethyl, and/or cyano.
As used herein, xe2x80x9clower alkoxyxe2x80x9d means the group xe2x80x94O-(lower alkyl) wherein lower alkyl is as defined herein.
As used herein xe2x80x9clower alkylxe2x80x9d refers to an alkyl radical having from 1 to 6 carbon atoms (C1-C6), such as, for example, methyl, ethyl, propyl, iso-propyl, tert-butyl, butyl, n-hexyl, and the like, unless otherwise indicated.
As used herein, xe2x80x9cpharmaceutically acceptablexe2x80x9d means suitable for use in a human or other mammal.
As used herein, xe2x80x9csafe and effective amount of a compoundxe2x80x9d (or composition, or the like) means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and/or reversing hair loss or promoting hair growth, at the site(s) of activity in a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
As used herein xe2x80x9csaltxe2x80x9d is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art. Preferred cationic salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts. Preferred anionic salts include the halides (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use.
The present invention relates to methods of treating hair loss comprising administering a composition comprising a compound having the structure: 
and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein:
(a) n is an integer from 1 to 3;
(b) R1 and R2 are each, independently, selected from hydrogen and lower alkyl; or wherein R1 is hydrogen and R2 is hydroxy; or wherein R1 is doubly-bonded oxygen and R2 is nil; or wherein R1 is doubly-bonded sulfur and R2 is nil;
(c) R4 is selected from hydrogen, lower alkyl, and cycloalkyl;
(d) R6 and R9 are each, independently, selected from hydrogen and lower alkyl;
(e) R7 and R8 are each, independently, selected from hydrogen, lower alkyl, optionally substituted phenyl, optionally substituted benzyl, and heteroaryl; wherein at least one of R7 and R8 is not hydrogen;
(f) R10 is selected from hydrogen, lower alkyl, cycloalkyl, and acyl;
(g) R11 is selected from hydrogen, lower alkyl, and cycloalkyl.
The compounds useful in the method herein are further described in Scanlan et al., WO 98/57919, assigned to The Regents of the University of California, published Dec. 23, 1998 and Scanlan et al., U.S. Pat. No. 5,883,294, The Regents of the University of California, issued Mar. 16, 1999. However, for convenience, the compounds are more fully described herein below:
The compounds useful in the present invention are dimethyl-substituted biphenyl compounds linked through a carbon atom linker, wherein the linker is optionally substituted with R1 and/or R2. Each of the phenyl rings of the biphenyl compound are substituted with at least one moiety, as is described below.
The R1 and R2 Moieties
R1 and R2 substituted on the carbon linker and are each, independently, selected from hydrogen and lower alkyl. Alternatively, R1 is hydrogen and R2 is hydroxy; or R1 is doubly-bonded oxygen (xe2x95x90O) and R2 is nil; or R1 is doubly-bonded sulfur (xe2x95x90S) and R2 is nil. Preferably, R1 is selected from methyl, hydrogen, and doubly-bonded oxygen. Preferably, R2 is selected from methyl and hydrogen. More preferably, at least one of R1 and R2 is hydrogen. Most preferably, R1 and R2 are each hydrogen.
The R4 Moiety
R4 may substitute at any available position on the designated phenyl ring. R4 is selected from hydrogen, lower alkyl, and cycloalkyl. Preferably, R4 is hydrogen.
The R6 and R9 Moieties
R6 and R9 are each, independently, selected from hydrogen and lower alkyl. Preferably, R6 and R9 are each, independently, selected from hydrogen and n-butyl. More preferably, at least one of R6 and R9 is hydrogen. Most preferably R6 and R9 are each hydrogen.
The R7 and R8 Moieties
R7 and R8 are each, independently, selected from hydrogen, lower alkyl, optionally substituted phenyl, optionally substituted benzyl, and heteroaryl; wherein at least one of R7 and R8 is not hydrogen. Preferably R7 and R8 are each, independently, selected from hydrogen and iso-propyl. More preferably, R7 is hydrogen and R8 is iso-propyl.
The R10 Moiety
The R10 moiety substitutes on the indicated oxygen atom. R10 is selected from hydrogen, lower alkyl, cycloalkyl, and acyl. Preferably R10 is selected from hydrogen and lower alkyl, preferably hydrogen and methyl. Most preferably, R10 is hydrogen.
The Integer n
The integer n determines the number of methylene groups in the respective moiety. The integer n is from 1 to 3, and is most preferably 1.
The R11 Moiety
The R11 moiety is selected from hydrogen, lower alkyl, and cycloalkyl. Preferably, R11 is selected from hydrogen and lower alkyl. Most preferably, R11 is hydrogen.
The present invention relates to methods of treating hair loss by administering a compound having a structure as described herein. Preferably, the compound utilized in the present invention will be cardiac-sparing. Compounds (test compounds) may be tested for their ability to induce anagen and their lack of cardiotoxicity (cardiac-sparing) using the following methods. Alternatively, other methods well-known in the art may be used (but with the term xe2x80x9ccardiac-sparingxe2x80x9d being defined according to the method disclosed herein below).
Cardiotoxicity Assay:
The cardiotoxicity assay measures the potential of a test compound to adversely affect the cardiovascular system. As thyroid hormone (T3) damages the cardiovascular system, the heart enlarges. See, e.g., Gomberg-Maitland et al., xe2x80x9cThyroid hormone and Cardiovascular Diseasexe2x80x9d, American Heart Journal, Vol. 135(2), pp. 187-196 (1998); Klein and Ojamaa, xe2x80x9cThyroid Hormone and the Cardiovascular Systemxe2x80x9d, Current Opinion in Endocrinology and Diabetes, Vol. 4, pp.341-346 (1997); and Klemperer et al., xe2x80x9cThyroid Hormone Therapy and Cardiovascular Diseasexe2x80x9d, Progress in Cardiovascular Diseases, Vol. 37 (4), pp. 329-336 (1996). This increases the weight of the heart relative to whole body weight. The cardiotoxicity assay herein below is used to test compounds for potentially adverse cardiac effects by measuring their effect on the heart-to-body weight ratio.
Two groups each of six male Sprague Dawley rats (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) (each weighing from approximately 220 grams to 235 grams) are utilized. The first group is a vehicle control group and the second group is a test compound group. The length of the assay is 30 days, with treatment of vehicle or test compound in vehicle daily for 28 of those days as described below.
Prior to initiation of the assay, each rat is allowed to acclimate to standard environmental conditions for 5 days. Each rat receives food (standard rat chow diet) and water ad libitum 5 days prior to initiation of the assay as well as to termination of the study.
The vehicle is 91:9 (v:v) propylene glycol:ethanol. The test compound is prepared at a concentration of 500 xcexcg/mL in the vehicle.
Each rat is weighed on day 1 of the assay. Dosage calculations are then performed: each rat will be administered daily a dosing solution of vehicle or test compound in vehicle (depending on whether the rat is in the vehicle control group or the test compound group, respectively) at 500 xcexcL of dosing solution per kg of rat. For rats in the test compound group, this corresponds to a dose of 250 xcexcg of test compound per kg of rat.
Day 2 is the first day of treatment with dosing solution for both groups. Body weights are taken for each rat on days 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, and 29 prior to dosing for that day; for each rat, the dosing solutions are recalculated and administered accordingly upon change in body weight.
Treatment occurs once daily in the morning on days 2 through 29, inclusive, for each rat in each group. For each treatment, the dosing solution is administered subcutaneously between the shoulders of the rat such that the injection sites are rotated in this area.
On day 30 in the morning, the rats of each group are euthanized with CO2 from dry ice. Each rat is immediately weighed for total body weight.
The hearts of each rat are then excised as follows. An incision is made to expose the abdominal cavity. The rib cage is carefully cut at the sternum with small scissors, such that the heart and lungs are exposed. With small scissors and forceps, the vessels connected to the heart are cut away from the heart. These vessels include the caudal vena cava, left cranial vena cava (pulmonary trunk), right cranial vena cava, thoracic aorta, right subclavian artery, internal thoracic artery and vein, and any other small attachments. The heart is then immediately taken out intact, including the left and right auricles and left and right ventricles. Immediately thereafter, any excess tissue is trimmed away, the heart is lightly blotted on a paper towel until no more blood is visibly left behind on the paper towel, and the heart is weighed.
The heart weight is divided by the body weight after euthanization for each rat to give the heart/body ratio. The heart/body ratios for each rat in the vehicle control group are added together and divided by 6 (i.e., the total number of rats in the group) to give RV (ratio for vehicle control group). Similarly, the heart/body ratios for each rat in the test compound group are added together and divided by 6 to give RT (ratio for test compound group).
The index C is then calculated by dividing RT by RV. As defined herein, where C is less than 1.3, the test compound is cardiac-sparing. Preferably, C is less than 1.2, more preferably less than 1.15, and most preferably less than 1.1. In accordance with this method, T3 and T4 are not cardiac-sparing.
Telogen Conversion Assay:
The Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle (xe2x80x9ctelogenxe2x80x9d), to the growth stage of the hair growth cycle (xe2x80x9canagenxe2x80x9d).
Without intending to be limited by theory, there are three principal phases of the hair growth cycle: anagen, catagen, and telogen. It is believed that there is a longer telogen period in C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized. Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth inducers are evaluated. The Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.
Three groups of 44 day-old C3H mice are utilized: a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound used in the method of the present invention. The length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly. A typical study design is shown in Table 1 below. Typical dosage concentrations are set forth in Table 1, however the skilled artisan will readily understand that such concentrations may be modified.
The mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib). A pipettor and tip are used to deliver 400 xcexcL to each mouse""s back. The 400 xcexcL application is applied slowly while moving hair on the mouse to allow the application to reach the skin.
While each treatment is being applied to the mouse topically, a visual grade of from 0 to 4 will be given to the skin color in the application area of each animal. As a mouse converts from telogen to anagen, its skin color will become more bluish-black. As indicated in Table 2, the grades 0 to 4 represent the following visual observations as the skin progresses from white to bluish-black.
The compounds used in the methods of the present invention are prepared according to procedures which are well-known to those ordinarily skilled in the art. The starting materials used in preparing the compounds are known, made by known methods, or are commercially available as a starting material.
It is recognized that the ordinarily skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction. Examples of such manipulations are discussed in standard texts such as J. March, Advanced Organic Chemistry, John Wiley and Sons (1992).
The ordinarily skilled artisan will readily appreciate that certain reactions are best carried out when other functionalities are masked or protected in the compound, thus increasing the yield of the reaction and/or avoiding any undesirable side reactions. Often, the artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and arc also well within the scope of the skilled artisan. Examples of many such manipulations can be found in, for example, T. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons (1981).
The compounds of the present invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography.
In addition, it is recognized that one optical isomer, including a diastereomer and enantiomer, or a stereoisomer, may have favorable properties over the other. Thus, when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
The syntheses of the compounds useful in the present invention are described in the art. Accordingly, the ordinarily skilled artisan will be able to prepare the compounds described herein. For further guidance, the syntheses of the present compounds are described in Scanlan et al., WO 98/57919, assigned to The Regents of the University of California, published Dec. 23, 1998 and Scanlan et al., U.S. Pat. No. 5,883,294, assigned to The Regents of the University of California, issued Mar. 16, 1999. For convenience, non-limiting syntheses of the compounds used herein are set forth in the examples below.